tbuckley/cabot-search huggingface dataset:
Circulating microRNAs and Cytokines as Prognostic Biomarkers for Doxorubicin-Induced Cardiac Injury and for Evaluating the Effectiveness of an Exercise Intervention
Authors: Prince Jeyabal, Anchit Bhagat, Fei Wang, Michael Roth, J. Andrew Livingston, Susan C. Gilchrist, Jose Banchs, Michelle A.T. Hildebrandt, Joya Chandra, Anita Deswal, Efstratios Koutroumpakis, Jian Wang, Najat C. Daw, Theresa A. Honey, Eugenie S. Kleinerman
Journal: Clinical Cancer Research (2023)

Abstract Purpose: To define a set of biomarkers that can be used to identify patients at high risk of developing late doxorubicin (DOX)-induced cardiac morbidity with the goal of focused monitoring and early interventions. Experimental Design: Mice received phosphate buffered saline or DOX 2.5 mg/kg 2x/week for 2 weeks. Blood samples were obtained before and after therapy for quantification of miRNAs (6 and 24 hours), cytokines (24 hours), and troponin (24 hours, 4 and 6 weeks). Cardiac function was evaluated using echocardiography before and 24 hours after therapy. To assess the effectiveness of exercise intervention in preventing DOX-induced cardiotoxicity blood samples were collected from mice treated with DOX or DOX + exercise. Plasma samples from 13 DOX-treated patients with sarcoma were also evaluated before and 24 hours after therapy. Results: Elevations in plasma miRNA-1, miRNA-499 and IL1α, IL1β, and IL6 were seen in DOX-treated mice with decreased ejection fraction and fractional shortening 24 hours after DOX therapy. Troponin levels were not elevated until 4 weeks after therapy. In mice treated with exercise during DOX, there was no elevation in these biomarkers and no change in cardiac function. Elevations in these biomarkers were seen in 12 of 13 patients with sarcoma treated with DOX. Conclusions: These findings define a potential set of biomarkers to identify and predict patients at risk for developing acute and late cardiovascular diseases with the goal of focused monitoring and early intervention. Further studies are needed to confirm the predictive value of these biomarkers in late cardiotoxicity.
Myeloid-specific KDM6B inhibition sensitizes glioblastoma to PD1 blockade
Authors: Sangeeta Goswami, Deblina Raychaudhuri, Pratishtha Singh, Seanu Meena Natarajan, Yulong Chen, Candice Poon, Mercedes Hennessey, Aminah J. Tannir, Jan Zhang, Swetha Anandhan, Brittany Parker Kerrigan, Marc D. Macaluso, Zhong He, Sonali Jindal, Frederick F. Lang, Sreyashi Basu, Padmanee Sharma
Journal: Nature Cancer (2023)
Extracellular vesicle pathogenic cues in systemic sclerosis: comment on the article by Mouawad et al
Authors: Ranjeet Singh Mahla
Journal: Arthritis & Rheumatology (2023)

Disclosure Form Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
The integrity of dopaminergic and noradrenergic brain regions is associated with different aspects of late-life memory performance
Authors: Martin J. Dahl, Shelby L. Bachman, Shubir Dutt, Sandra Düzel, Nils C. Bodammer, Ulman Lindenberger, Simone Kühn, Markus Werkle-Bergner, Mara Mather
Journal: Nature Aging (2023)

Abstract Changes in dopaminergic neuromodulation play a key role in adult memory decline. Recent research has also implicated noradrenaline in shaping late-life memory. However, it is unclear whether these two neuromodulators have distinct roles in age-related cognitive changes. Here, combining longitudinal MRI of the dopaminergic substantia nigra–ventral tegmental area (SN-VTA) and noradrenergic locus coeruleus (LC) in younger ( n = 69) and older ( n = 251) adults, we found that dopaminergic and noradrenergic integrity are differentially associated with memory performance. While LC integrity was related to better episodic memory across several tasks, SN-VTA integrity was linked to working memory. Longitudinally, we found that older age was associated with more negative change in SN-VTA and LC integrity. Notably, changes in LC integrity reliably predicted future episodic memory. These differential associations of dopaminergic and noradrenergic nuclei with late-life cognitive decline have potential clinical utility, given their degeneration in several age-associated diseases.
A defect in mitochondrial fatty acid synthesis impairs iron metabolism and causes elevated ceramide levels
Authors: Debdeep Dutta, Oguz Kanca, Seul Kee Byeon, Paul C. Marcogliese, Zhongyuan Zuo, Rishi V. Shridharan, Jun Hyoung Park, Guang Lin, Ming Ge, Gali Heimer, Jennefer N. Kohler, Matthew T. Wheeler, Benny A. Kaipparettu, Akhilesh Pandey, Hugo J. Bellen
Journal: Nature Metabolism (2023)
Nociplastic pain: the wolf in sheep's clothing. Comment on the article by Sunzini et al
Authors: Roland Staud, Melyssa M. Godfrey, Patrick W. Stroman
Journal: Arthritis & Rheumatology (2023)

Disclosure form Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Impact of the WHO "best buys" for alcohol policy on consumption and health in the Baltic countries and Poland 2000–2020
Authors: Jürgen Rehm, Robertas Badaras, Carina Ferreira-Borges, Lukas Galkus, Nijole Gostautaite Midttun, Inese Gobiņa, Kinga Janik-Koncewicz, Domantas Jasilionis, Huan Jiang, Kawon Victoria Kim, Shannon Lange, Vaida Liutkutė-Gumarov, Jakob Manthey, Laura Miščikienė, Maria Neufeld, Janina Petkevičienė, Ričardas Radišauskas, Rainer Reile, Robin Room, Relika Stoppel, Ilona Tamutienė, Alexander Tran, Justina Trišauskė, Mateusz Zatoński, Witold A. Zatoński, Ingrida Zurlytė, Mindaugas Štelemėkas
Journal: The Lancet Regional Health - Europe (2023)

Alcohol use is a major risk factor for burden of disease. This narrative review aims to document the effects of major alcohol control policies, in particular taxation increases and availability restrictions in the three Baltic countries (Estonia, Latvia, and Lithuania) between 2000 and 2020. These measures have been successful in curbing alcohol sales, in general without increasing consumption of alcoholic beverages from unrecorded sources; although for more recent changes this may have been partly due to the COVID-19 pandemic. Moreover, findings from time-series analyses suggest improved health, measured as reductions in all-cause and alcohol-attributable mortality, as well as narrowing absolute mortality inequalities between lower and higher educated groups. For most outcomes, there were sex differences observed, with alcohol control policies more strongly affecting males. In contrast to this successful path, alcohol control policies were mostly dismantled in the neighbouring country of Poland, resulting in a rising death toll due to liver cirrhosis and other alcohol-attributable deaths. The natural experiment in this region of high-income European countries with high consumption levels highlights the importance of effective alcohol control policies for improving population health.
Multimodal Imaging of Corneal Manifestation of Siderosis Bulbi
Authors: Somya Kumari, Neha Kumari, Adithi K. Murthy
Journal: Ophthalmology (2023)

An 18-year-old man presented with gradual reduction of vision in his right eye for 3 months to 20/40 after sustaining trauma while working with a hammer and chisel. He underwent pars plana vitrectomy and foreign body removal. Siderosis had already set in, sparing the macula. Rust-colored cornea (A) due to intrastromal and subendothelial brownish deposition (A, slit section) was noted. Anterior-segment OCT showed hyperreflectivity within all corneal layers (B). Confocal imaging showed iron deposition in the basal layer of the epithelium (C, upper), anterior (C, middle), and posterior stroma (C, lower), and siderosomes as hyperreflective structures inside keratocytes (arrow, C). (Magnified version of Figure A-C is available online at www.aaojournal.org).
Predicting early bactericidal activity using pre-clinical data for tuberculosis drugs: a platform for model-informed drug discovery and development
Authors: Sophie L. Stocker, Jan-Willem C. Alffenaar
Journal: European Respiratory Journal (2023)

<h3>Tweetable abstract</h3> <b>Combining PK-PD data from animal models and the hollow-fibre system model in conjunction with human PK data in a platform has the ability to accelerate pre-clinical drug development and predict the dosages likely to be successful in human clinical trials</b>https://bit.ly/3K7IPcI
Use of Mitomycin C in Dacryocystorhinostomy
Authors: Suzanne K. Freitag, Vinay K. Aakalu, Jill A. Foster, Timothy J. McCulley, Jeremiah P. Tao, M. Reza Vagefi, Michael T. Yen, Stephen J. Kim, Edward J. Wladis
Journal: Ophthalmology (2023)
Precision modulation of dysbiotic adult microbiomes with a human-milk-derived synbiotic reshapes gut microbial composition and metabolites
Authors: Julie E. Button, Casey M. Cosetta, Abigail L. Reens, Sarah L. Brooker, Aislinn D. Rowan-Nash, Richard C. Lavin, Russell Saur, Shuning Zheng, Chloe A. Autran, Martin L. Lee, Adam K. Sun, Amin M. Alousi, Christine B. Peterson, Andrew Y. Koh, David J. Rechtman, Robert R. Jenq, Gregory J. McKenzie
Journal: Cell Host & Microbe (2023)
BMAL1 loss in oligodendroglia contributes to abnormal myelination and sleep
Authors: Daniela Rojo, Louisa Dal Cengio, Anna Badner, Samuel Kim, Noriaki Sakai, Jacob Greene, Tess Dierckx, Lindsey C. Mehl, Ella Eisinger, Julia Ransom, Caroline Arellano-Garcia, Mohammad E. Gumma, Rebecca L. Soyk, Cheyanne M. Lewis, Mable Lam, Maya K. Weigel, Valentina Martinez Damonte, Belgin Yalçın, Samuel E. Jones, Hanna M. Ollila, Seiji Nishino, Erin M. Gibson
Journal: Neuron (2023)
Targeting nucleic acid sensors in tumor cells to reprogram biogenesis and RNA cargo of extracellular vesicles for T cell-mediated cancer immunotherapy
Authors: Simon Heidegger, Florian Stritzke, Sarah Dahl, Juliane Daßler-Plenker, Laura Joachim, Dominik Buschmann, Kaiji Fan, Carolin M. Sauer, Nils Ludwig, Christof Winter, Stefan Enssle, Suqi Li, Markus Perl, André Görgens, Tobias Haas, Erik Thiele Orberg, Sascha Göttert, Catherine Wölfel, Thomas Engleitner, Isidro Cortés-Ciriano, Roland Rad, Wolfgang Herr, Bernd Giebel, Jürgen Ruland, Florian Bassermann, Christoph Coch, Gunther Hartmann, Hendrik Poeck
Journal: Cell Reports Medicine (2023)

Tumor-derived extracellular vesicles (EVs) have been associated with immune evasion and tumor progression. We show that the RNA-sensing receptor RIG-I within tumor cells governs biogenesis and immunomodulatory function of EVs. Cancer-intrinsic RIG-I activation releases EVs, which mediate dendritic cell maturation and T cell antitumor immunity, synergizing with immune checkpoint blockade. Intact RIG-I, autocrine interferon signaling, and the GTPase Rab27a in tumor cells are required for biogenesis of immunostimulatory EVs. Active intrinsic RIG-I signaling governs composition of the tumor EV RNA cargo including small non-coding stimulatory RNAs. High transcriptional activity of EV pathway genes and RIG-I in melanoma samples associate with prolonged patient survival and beneficial response to immunotherapy. EVs generated from human melanoma after RIG-I stimulation induce potent antigen-specific T cell responses. We thus define a molecular pathway that can be targeted in tumors to favorably alter EV immunomodulatory function. We propose "reprogramming" of tumor EVs as a personalized strategy for T cell-mediated cancer immunotherapy.
Brain-region-specific changes in neurons and glia and dysregulation of dopamine signaling in Grin2a mutant mice
Authors: Zohreh Farsi, Ally Nicolella, Sean K. Simmons, Sameer Aryal, Nate Shepard, Kira Brenner, Sherry Lin, Linnea Herzog, Sean P. Moran, Katherine J. Stalnaker, Wangyong Shin, Vahid Gazestani, Bryan J. Song, Kevin Bonanno, Hasmik Keshishian, Steven A. Carr, Jen Q. Pan, Evan Z. Macosko, Sandeep Robert Datta, Borislav Dejanovic, Eunjoon Kim, Joshua Z. Levin, Morgan Sheng
Journal: Neuron (2023)

A genetically valid animal model could transform our understanding of schizophrenia (SCZ) disease mechanisms. Rare heterozygous loss-of-function (LoF) mutations in GRIN2A, encoding a subunit of the NMDA receptor, greatly increase the risk of SCZ. By transcriptomic, proteomic, and behavioral analyses, we report that heterozygous Grin2a mutant mice show (1) large-scale gene expression changes across multiple brain regions and in neuronal (excitatory and inhibitory) and non-neuronal cells (astrocytes and oligodendrocytes), (2) evidence of hypoactivity in the prefrontal cortex (PFC) and hyperactivity in the hippocampus and striatum, (3) an elevated dopamine signaling in the striatum and hypersensitivity to amphetamine-induced hyperlocomotion (AIH), (4) altered cholesterol biosynthesis in astrocytes, (5) a reduction in glutamatergic receptor signaling proteins in the synapse, and (6) an aberrant locomotor pattern opposite of that induced by antipsychotic drugs. These findings reveal potential pathophysiologic mechanisms, provide support for both the "hypo-glutamate" and "hyper-dopamine" hypotheses of SCZ, and underscore the utility of Grin2a-deficient mice as a genetic model of SCZ.
Vinblastine resets tumor-associated macrophages toward M1 phenotype and promotes antitumor immune response
Authors: Yi-Na Wang, Yuan-Yuan Wang, Jin Wang, Wen-Juan Bai, Nai-Jun Miao, Jing Wang
Journal: Journal for ImmunoTherapy of Cancer (2023)

Massive tumor-associated macrophage (TAM) infiltration is observed in many tumors, which usually display the immune-suppressive M2-like phenotype but can also be converted to an M1-like antitumor phenotype due to their high degree of plasticity. The macrophage polarization state is associated with changes in cell shape, macrophage morphology is associated with activation status. M1 macrophages appeared large and rounded, while M2 macrophages were stretched and elongated cells. Manipulating cell morphology has been shown to affect the polarization state of macrophages. The shape of the cell is largely dependent on cytoskeletal proteins, especially, microtubules. As a microtubule-targetting drug, vinblastine (VBL) has been used in chemotherapy. However, no study to date has explored the effect of VBL on TAM shape changes and its role in tumor immune response.We used fluorescent staining of the cytoskeleton and quantitative analysis to reveal the morphological differences between M0, M1, M2, TAM and VBL-treated TAM. Flow cytometry was used to confirm the polarization states of these macrophages using a cell surface marker-based classification. In vivo antibody depletion experiments in tumor mouse models were performed to test whether macrophages and CD8+ T cell populations were required for the antitumor effect of VBL. VBL and anti-PD-1 combination therapy was then investigated in comparison with monotherapy. RNA-seq of TAM of treated and untreated with VBL was performed to explore the changes in pathway activities. siRNA mediated knockdown experiments were performed to verify the target pathway that was affected by VBL treatment.Here, we showed that VBL, an antineoplastic agent that destabilizes microtubule, drove macrophage polarization into the M1-like phenotype both in vitro and in tumor models. The antitumor effect of VBL was attenuated in the absence of macrophages or CD8+ T cells. Mechanistically, VBL induces the activation of NF-κB and Cyba-dependent reactive oxygen species generation, thus polarizing TAMs to the M1 phenotype. In parallel, VBL promotes the nuclear translocation of transcription factor EB, inducing lysosome biogenesis and a dramatic increase in phagocytic activity in macrophages.This study explored whether manipulating cellular morphology affects macrophage polarization and consequently induces an antitumor response. Our data reveal a previously unrecognized antitumor mechanism of VBL and suggest a drug repurposing strategy combining VBL with immune checkpoint inhibitors to improve malignant tumor immunotherapy.
On the Origins of Phenotypic Parallelism in Benthic and Limnetic Stickleback
Authors: Laura L Dean, Isabel Santos Magalhaes, Daniele D’Agostino, Paul Hohenlohe, Andrew D C MacColl
Journal: Molecular Biology and Evolution (2023)

Rapid evolution of similar phenotypes in similar environments, giving rise to in situ parallel adaptation, is an important hallmark of ecological speciation. However, what appears to be in situ adaptation can also arise by dispersal of divergent lineages from elsewhere. We test whether two contrasting phenotypes repeatedly evolved in parallel, or have a single origin, in an archetypal example of ecological adaptive radiation: benthic-limnetic three-spined stickleback (Gasterosteus aculeatus) across species pair and solitary lakes in British Columbia. We identify two genomic clusters across freshwater populations, which differ in benthic-limnetic divergent phenotypic traits and separate benthic from limnetic individuals in species pair lakes. Phylogenetic reconstruction and niche evolution modeling both suggest a single evolutionary origin for each of these clusters. We detected strong phylogenetic signal in benthic-limnetic divergent traits, suggesting that they are ancestrally retained. Accounting for ancestral state retention, we identify local adaptation of body armor due to the presence of an intraguild predator, the sculpin (Cottus asper), and environmental effects of lake depth and pH on body size. Taken together, our results imply a predominant role for retention of ancestral characteristics in driving trait distribution, with further selection imposed on some traits by environmental factors.
EPIC-1042 as a potent PTRF/Cavin1–caveolin-1 interaction inhibitor to induce PARP1 autophagic degradation and suppress temozolomide efflux for glioblastoma
Authors: Biao Hong, Eryan Yang, Dongyuan Su, Jiasheng Ju, Xiaoteng Cui, Qixue Wang, Fei Tong, Jixing Zhao, Shixue Yang, Chunchao Cheng, Lei Xin, Menglin Xiao, Kaikai Yi, Qi Zhan, Yaqing Ding, Hanyi Xu, Longtao Cui, Chunsheng Kang
Journal: Neuro-Oncology (2023)

Abstract Background Temozolomide (TMZ) treatment efficacy in glioblastoma is determined by various mechanisms such as TMZ efflux, autophagy, base excision repair (BER) pathway, and the level of O6-methylguanine-DNA methyltransferase (MGMT). Here, we reported a novel small-molecular inhibitor (SMI) EPIC-1042 (C20H28N6) with the potential to decrease TMZ efflux and promote PARP1 degradation via autolysosomes in the early stage. Methods EPIC-1042 was obtained from receptor-based virtual screening. Co-immunoprecipitation and pull-down assays were applied to verify the blocking effect of EPIC-1042. Western blotting, co-immunoprecipitation, and immunofluorescence were used to elucidate the underlying mechanisms of EPIC-1042. In vivo experiments were performed to verify the efficacy of EPIC-1042 in sensitizing glioblastoma cells to TMZ. Results EPIC-1042 physically interrupted the interaction of PTRF/Cavin1 and caveolin-1, leading to reduced secretion of small extracellular vesicles (sEVs) to decrease TMZ efflux. It also induced PARP1 autophagic degradation via increased p62 expression that more p62 bound to PARP1 and specially promoted PARP1 translocation into autolysosomes for degradation in the early stage. Moreover, EPIC-1042 inhibited autophagy flux at last. The application of EPIC-1042 enhanced TMZ efficacy in glioblastoma in vivo. Conclusion EPIC-1042 reinforced the effect of TMZ by preventing TMZ efflux, inducing PARP1 degradation via autolysosomes to perturb the BER pathway and recruitment of MGMT, and inhibiting autophagy flux in the later stage. Therefore, this study provided a novel therapeutic strategy using the combination of TMZ with EPIC-1042 for glioblastoma treatment.
Epidemiology and survival of adult-type diffuse glioma in Belgium during the molecular era
Authors: Harry Pinson, Geert Silversmit, Dimitri Vanhauwaert, Katrijn Vanschoenbeek, Jean-Pierre Kalala Okito, Steven De Vleeschouwer, Tom Boterberg, Cindy De Gendt
Journal: Neuro-Oncology (2023)

Survival data of diffuse adult-type glioma is mostly based on prospective clinical trials or small retrospective cohort studies. Real-world data with large patient cohorts is currently lacking.
Using Machine Learning to Predict <i>TP53</i> Mutation Status and Aggressiveness of Prostate Cancer from Routine Histology Images
Authors: François Bordeleau
Journal: Cancer Research (2023)

Abstract Despite years of progress, we still lack reliable tools to predict the aggressiveness of tumors, including in the case of prostate cancer. Biomarkers have been developed, but they often suffer from poor accuracy if used alone due to tumor heterogeneity. Nevertheless, some mutations, notably TP53 mutations, are highly correlated with progression. In their work in this issue of Cancer Research, Pizurica and colleagues implemented a machine learning–based model applied to routine histology and trained with prior information on TP53 mutation status. Their model output provides a quantitative prediction of TP53 mutation status while having a strong correlation with aggressiveness, showing promise as a prognostic in silico biomarker. See related article by Pizurica et al., p. 2970
MRD and Plasma Cell Dynamics after CAR T-cell Therapy in Myeloma
Authors: Ola Landgren, Dickran Kazandjian
Journal: Blood Cancer Discovery (2023)

Summary: In this issue, Paiva and colleagues characterize the dynamics of minimal residual disease (MRD) and clinical responses during chimeric antigen receptor (CAR) T-cell therapy of relapsed/refractory multiple myeloma. Although both correlate with prolonged progression-free survival, MRD is reached faster in the bone marrow than complete response in peripheral blood; consequently, the study addresses the need for future guidelines to explore new MRD-negative definitions that are independent of the monoclonal (M) protein to overcome this limitation, particularly in clinical trials using early depth of response as an endpoint. See related article by Paiva et al., p. 365 (1).